Research Notes: Genes - Imprinted in Prader-Willi Syndrome (IPW)

• Entrez Gene | OMIM
• paternally imprinted
• expressed predominantly in brain

Genet Med. 1999 May-Jun.
Analysis of imprinted genes in subjects with Prader-Willi syndrome and chromosome 15 abnormalities.
Muralidhar B, Marney A, Butler MG.
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

PURPOSE: To determine gene expression of five imprinted genes or transcripts from the 15q11-q13 chromosome region using reverse transcription polymerase chain reaction (RT-PCR) in a relatively large survey of Prader-Willi syndrome (PWS) and control subjects with several different chromosome 15 abnormalities. METHODS: RT-PCR was undertaken on mRNA isolated from tissue (e.g., mostly lymphoblasts) from 38 PWS and 10 control subjects. DNA primers were used for five imprinted genes or transcripts (ZNF127, SNRPN, PAR5, IPW, and PAR1) from 15q11-q13 and fibrillin, a control gene from 15q21. RESULTS: One PWS subject with maternal disomy 15 showed weak but detectable expression of PAR1, whereas SNRPN expression was detected in two PWS subjects [one with the 15q11-q13 deletion and one with a t(15;15) karyotype and maternal disomy 15], and the remaining typical PWS subjects showed no expression of the imprinted genes or transcripts. CONCLUSION: No obvious clinical differences were identified in those PWS subjects with weak expression of genes compared with those showing no expression. Although the reason(s) for weak expression is unknown, possible explanations include relaxation of imprinting caused by failure to reset the imprinted genes or transcripts in the maternal germ line or by postzygotic gene expression or undetected chromosome 15 mosaicism in the deletion PWS subjects. The timing, tissue source, and other factors relating to partial expression of genes that are thought to be imprinted may play a role in clinical variability and allow for a better understanding of molecular mechanisms in PWS and other abnormalities of proximal chromosome 15q.

Novartis Found Symp. 1998.
Imprinted genes in the Prader-Willi deletion.
Francke U.
Department of Genetics, Beckman Center for Molecular and Genetic Medicine, CA, USA.

Parent-of-origin-specific deletions of proximal chromosome 15q cause either the Prader-Willi syndrome (paternal deletion) or the Angelman syndrome (maternal deletion), two distinct neurodevelopmental disorders. In contrast to the Angelman syndrome, which can also be caused by mutations in a single gene (UBE3A, encoding a ubiquitin ligase), the Prader-Willi syndrome is caused by deletions in about two-thirds of cases and by maternal uniparental disomy in the remaining third. The consequence of both mechanisms, in addition to rare microdeletions or so-called 'imprinting mutations', is lack of the products of multiple genes in the region that are normally expressed only from the paternal chromosome. One gene that is consistently silent in the Prader-Willi syndrome is SNRPN, which encodes the small nuclear ribonucleoprotein particle-associated polypeptide N that forms part of the spliceosomes in the brain. A systematic search for other imprinted genes in the Prader-Willi syndrome region revealed a paternally expressed transcript (IPW, for imprinted in the Prader-Willi region) and a similarly imprinted mouse homologue (Ipw) in the conserved syntenic region on mouse chromosome 7. Ipw is highly expressed in the brain and alternatively spliced to generate different transcripts. Since there is no open reading frame that is conserved in the human and mouse IPW genes, they are postulated to function as untranslated RNAs, possibly regulating transcription in cis in the region.

Hum Mol Genet. 1994 Oct.
Identification of a novel paternally expressed gene in the Prader-Willi syndrome region.
Wevrick R, Kerns JA, Francke U.
Department of Genetics, Stanford University, CA.

We have isolated a novel gene from the Prader-Willi syndrome (PWS) smallest region of deletion overlap in proximal human chromosome 15q. IPW (Imprinted gene in the Prader-Willi syndrome region) was isolated using the direct selection method and yeast artificial chromosomes localized to the deletion region. IPW is spliced and polyadenylated but its longest open reading frame codes for only 45 amino acids, suggesting that it functions as an RNA, similar to H19 and XIST. The RNA is widely expressed in adult and fetal tissues and is found in the cytoplasmic fraction of human cells, which is also the case for the H19 non-translated RNA, but differs from the XIST RNA which is found predominantly in the nucleus. Using a sequence polymorphism, exclusive expression from the paternal allele in lymphoblasts and fibroblasts was demonstrated; monoallelic expression was found in fetal tissues. IPW is located about 150 kb distal to SNRPN, the only other known gene in the deletion interval, and about 50 kb proximal to the breakpoint of a translocation which defines the distal end of the PWS region and the proximal end of the Angelman syndrome (AS) region. As is the case with SNRPN, PWS patients with 15q11-q13 deletions do not express IPW, whereas expression is normal in Angelman syndrome patients. Lack of expression of IPW may contribute to the PWS phenotype directly. Alternatively, the mRNA product of IPW may play a role in the imprinting process, acting either on genes located proximally in the PWS region or distally in the AS region.